Interleukin-6 (IL-6)
Interleukin-6 (“IL-6”) is a multifunctional cytokine involved in numerous biological processes such as the regulation of the acute inflammatory response, the modulation of specific immune responses including B- and T-cell differentiation, bone metabolism, thrombopoiesis, epidermal proliferation, menses, neuronal cell differentiation, neuroprotection, aging, cancer, and the inflammatory reaction occurring in Alzheimer's disease. See Papassotiropoulos, et al. (2001) Neurobiology of Aging 22: 863-871.
IL-6 is a member of a family of cytokines that promote cellular responses through a receptor complex consisting of at least one subunit of the signal-transducing glycoprotein gp130 and the IL-6 receptor (“IL-6R”) (also known as gp80). The IL-6R may also be present in a soluble form (“sIL-6R”). IL-6 binds to IL-6R, which then dimerizes the signal-transducing receptor gp130. See Jones (2005) Immunology 175: 3463-3468.
IL-6 is a pleiotropic pro-inflammatory cytokine, which regulates the acute phase response and the transition from the innate to the adaptive immune response. IL-6 increases hepatic synthesis of proteins that are involved in the ‘acute phase response’ leading to symptoms such as fever, chills, and fatigue. It stimulates B cell differentiation and secretion of antibodies and prevents apoptosis of activated B cells. IL-6 activates and induces proliferation of T cells and in the presence of IL-2, induces differentiation of mature and immature CD8 T cells into cytotoxic T cells. IL-6 is also involved in the differentiation of Th17 cells and IL-17 production and inhibits regulatory T cells (Treg) differentiation. IL-6 also activates osteoclasts, synoviocytes, neutrophils, and other hematopoietic cells. Park, et al. (2007) Bulletin of the NYU Hospital for Joint Diseases 65 (suppl 1): S4-10; Guerne, et al. (1989) J Clin Invest. 83(2): 585-92; Houssiau, et al. (1988) Arthritis Rheum. 31(6): 784-8; Nishimotor, et al. (2006) Nat Clin Pract Rheumatol. 2(11): 619-26; Kishimoto (1989) Blood 74(1): 1-10; and Van Snick (1990) Annu Rev Immunol. 8: 253-78.
In humans, the gene encoding IL-6 is organized in five exons and four introns, and maps to the short arm of chromosome 7 at 7p21. Translation of IL-6 RNA and post-translational processing result in the formation of a 21 to 28 kDa protein with 184 amino acids in its mature form. See Papassotiropoulos, et al. (2001) Neurobiology of Aging 22:863-871.
The function of IL-6 is not restricted to the immune response as it acts in hematopoiesis, thrombopoiesis, osteoclast formation, elicitation of hepatic acute phase response resulting in the elevation of C-reactive protein (CRP) and serum amyloid A (SAA) protein. It is known to be a growth factor for epidermal keratinocytes, renal mesangial cells, myeloma and plasmacytoma cells. Grossman, et al. (1989) Prot Natl Acad Sci. 86(16): 6367-6371; Horii, et al. (1989) J Immunol. 143(12): 3949-3955; and Kawano, et al. (1988) Nature 332: 83-85. IL-6 is produced by a wide range of cell types including monocytes/macrophages, fibroblasts, epidermal keratinocytes, vascular endothelial cells, renal messangial cells, glial cells, condrocytes, T and B-cells and some tumor cells. Akira, et al. (1990) FASEB J. 4(11): 2860-2867. Except for tumor cells that constitutively produce IL-6, normal cells do not express IL-6 unless appropriately stimulated.
Elevated IL-6 levels have been observed in many types of cancer, including breast cancer, leukemia, ovarian cancer, prostate cancer, pancreatic cancer, lymphoma, lung cancer, renal cell carcinoma, colorectal cancer, and multiple myeloma. See, e.g., Chopra, et al. (2004) MJAFI 60:45-49; Songur, et al. (2004) Tumori 90:196-200; Blay, et al. (1992) Cancer Research 52: 3317-3322; Nikiteas, et al. (2005) World J. Gasterenterol. 11:1639-1643; reviewed in Heikkila, et al. (2008) Eur J Cancer 44:937-945. Clinical studies (reviewed in Trikha, et al. (2003) Clinical Cancer Research 9: 4653-4665) have shown some improvement in patient outcomes due to administration of various anti-IL-6 antibodies, particularly in those cancers in which IL-6 plays a direct role promoting cancer cell proliferation or survival.
As noted above, IL-6 stimulates the hepatic acute phase response, resulting in increased production of CRP and elevated serum CRP levels. For this reason, C-reactive protein (CRP) has been reported to comprise a surrogate marker of IL-6 activity. Thus, elevated IL-6 activity can be detected through measurement of serum CRP. Conversely, effective suppression of IL-6 activity, e.g., through administration of a neutralizing anti-IL-6 antibody, can be detected by the resulting decrease in serum CRP levels.
IL-6 is believed to play a role in the development of a, multitude of diseases and disorders, including but not limited to fatigue, cachexia, autoimmune diseases, diseases of the skeletal system, cancer, heart disease, obesity, diabetes, asthma, Alzheimer's disease and multiple sclerosis. See, e.g., WO 2011/066374, WO 2011/066371, WO 2011/066378, and WO 2011/066369.
A recent clinical trial demonstrated that administration of rosuvastatin to apparently healthy individuals having elevated CRP (greater than 2.0 mg/l) reduced their CRP levels by 37% and greatly decreased the incidence of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. Ridker et al., N Engl J Med. 2008 Nov. 9 [Epub ahead of print].
In addition to its direct role in pathogenesis of some cancers and other diseases, chronically elevated IL-6 levels appear to adversely affect patient well-being and quality of life. For example, elevated IL-6 levels have been reported to be associated with cachexia and fever, and reduced serum albumin. Gauldie, et al. (1987) PNAS 84: 7251-7253; Heinric, et al. (1990) Biochem J. 265(3): 621-636; Zamir, et al. (1993) Metabolism 42: 204-208; Zamir, et al. (1992) Arch Surg 127: 170-174. Inhibition of IL-6 by a neutralizing antibody has been reported to ameliorate fever and cachexia in cancer patients, though improvement in these patients' serum albumin level has not been reported. Emilie, et al. (1994) Blood 84: 2472-2479; Slay, et al. (1992) Cancer Research 52: 3317-3322; Bataille, et al. (1995) Blood 86: 685-691.
Rheumatoid Arthritis
Reumatoid arthritis (RA) is a long-term disease that leads to inflammation of the joints and surrounding tissues but can also affect other organs. The cause of RA is unknown but is known to be an autoimmune disease where the immune system mistakenly attacks healthy tissue. RA can occur at any age, but is more common in middle age. Women get RA more often than men. A.D.A.M. Medical Encylopedia (2011) U.S. National Library of Medicine.
RA usually affects joints on both sides of the body equally where the wrists, fingers, knees, feet, and ankles are the most commonly affected. The disease often begins slowly, usually with only minor joint pain, stiffness, and fatigue. Joint symptoms may include: Morning stiffness, which lasts more than 1 hour, is common. Joints may feel warm, tender, and stiff when not used for an hour; Joint pain is often felt on the same joint on both sides of the body; and Over time, joints may lose their range of motion and may become deformed. Other symptoms of RA include: chest pain when taking a breath (pleurisy); dry eyes and mouth (Sjogren syndrome); eye burning, itching, and discharge; nodules under the skin (usually a sign of more severe disease); and numbness, tingling, or burning in the hands and feet. A.D.A.M. Medical Encylopedia (2011) U.S. National Library of Medicine.
Two common lab tests that help in the diagnosis of RA are Rheumatoid factor test and the anti-CCP antibody test. Other tests that may be used in the diagnosis of RA include: Complete blood count; C-reactive protein; erythrocyte sedimentation rate; joint ultrasound or MRI; Joint x-rays; and synovial fluid analysis. A.D.A.M. Medical Encylopedia (2011) U.S. National Library of Medicine.
RA usually requires lifelong treatment, including medications, physical therapy, exercise, education, and possibly surgery. Early, aggressive treatment for RA can delay joint destruction. Disease modifying antirheumatic drugs (DMARDs) are commonly used to treat RA including Methotrexate (Rheumatrex), Leflunomide (Arava) and sulfasalazine. Unfortunately, these drugs may have serious side effects. Anti-inflammatory medications include aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naprosen. Although NSAIDs may work, long-term use can cause stomach problems, such as ulcers and bleeding, and possible heart problems. Celecoxib (Celebrex) is another anti-inflammatory drug, but it is labeled with strong warnings about heart disease and stroke. Antimalarial medications include hydroxychloroquine (Plaquenil) and sulfasalazine (Azulfidine), and is usually used along with methotrexate. It may be weeks or months before you see any benefit from these medications. Corticosteroids may assist in reducing joint swelling and inflammation but because of long-term side effects, corticosteroids should be taken only for a short time and in low doses when possible. A.D.A.M. Medical Encylopedia (2011) U.S. National Library of Medicine.
Biologic drugs are available that are designed to affect parts of the immune system that play a role in the disease process of rheumatoid arthritis. Biologic agents include White blood cell modulators include: abatacept (Orencia) and rituximab (Rituxan); Tumor necrosis factor (TNF) inhibitors include: adalimumab (Humira), etanercept (Enbrel), infliximab (Remicade), golimumab (Simponi), and certolizumab (Cimzia); and Interleukin-6 (IL-6) inhibitors: tocilizumab (Aetemra) Biologic agents may be used to treat rheumatoid arthritis, but they may have serious risk factors such as infections from bacteria, viruses, and fungi; leukemia or lymphoma; and psoriasis. A.D.A.M. Medical Encylopedia (2011) U.S. National Library of Medicine.
Occasionally, surgery is needed to correct severely damaged joints. Surgery may including the removal of the joint lining (synovectomy) and total joint replacement in extreme cases; may include total knee, hip replacement, ankle replacement, shoulder replacement, and others. A.D.A.M. Medical Encylopedia (2011) U.S. National Library of Medicine.
Physical therapy such as range-of-motion exercises and exercise programs prescribed by a physical therapist can delay the loss of joint function and help keep muscles strong. Sometimes therapists will use special machines to apply deep heat or electrical stimulation to reduce pain and improve joint movement. Joint protection techniques, heat and cold treatments, and splints or orthotic devices to support and align joints may be very helpful. To manage RA, frequent rest periods between activities, as well as 8 to 10 hours of sleep per night, are recommended. A.D.A.M. Medical Encylopedia (2011) U.S. National Library of Medicine.
Patients with rheumatoid factor, the anti-CCP antibody, or subcutaneous nodules are at risk to have a more severe form of the disease. People who develop RA at younger ages also may develop a more serious form of RA. A.D.A.M. Medical Encylopedia (2011) U.S. National Library of Medicine.
Rheumatoid arthritis can affect nearly every part of the body. Complications may include damage to the lung tissue (rheumatoid lung); increased risk of hardening of the arteries; spinal injury when the neck bones become damaged; inflammation of the blood vessels (rheumatoid vasculitis), which can lead to skin, nerve, heart, and brain problems; and swelling and inflammation of the outer lining of the heart (pericarditis) and of the heart muscle (myocarditis), which can lead to congestive heart failure. A.D.A.M. Medical Encylopedia (2011) U.S. National Library of Medicine.
The current treatments for RA can also cause serious side effects. Therefore, there is a strong need in the art for improved methods of treating and preventing rheumatoid arthritis.